1. Field of the Invention
The present invention relates generally to the fields of kinase inhibitors, transcription and virology. More particularly, it concerns the surprising discovery that flavopiridol dramatically inhibits the transcription elongation factor, P-TEFb. As P-TEFb is essential for HIV productive infection, the present invention provides new, effective methods, compositions and kits for treating HIV infections and AIDS using flavopiridol and combinations thereof.
2. Description of Related Art
The Human Immunodeficiency Virus (HIV) is a retrovirus that productively infects human and primate cells. In humans, infection with HIV is life-threatening and leads to AIDS, the terminal syndrome due to HIV infection. Although HIV has been the subject of intense biomedical and clinical research, there are still few effective therapies for use against HIV infection and AIDS. In certain areas of the world, HIV is particularly prevalent; for example, in Africa, one out of every four adults reportedly carries the HIV virus. HIV infection, and the resultant AIDS syndrome, are thus unfortunately widespread and continue to exert a significant toll in human suffering and economic terms.
There are about 15 therapeutics currently approved for administration to patients with HIV. Most of these are either protease inhibitors, such as Saquinavir, the first protease inhibitor approved for treatment of HIV (under the name, Invirase(trademark)); or nucleoside reverse transcriptase inhibitors, including AZT (marketed as Retrovir(trademark)). Unfortunately, the effectiveness of even the most potent and specific drugs, those that inhibit a required HIV protease, is limited as resistant strains arise quickly. In fact, treatment with current drugs has been reported to stimulate the selection and propagation of resistant viral strains. It has therefore been suggested that the most effective treatments are those incorporating a combinatorial use of different drugs. However, these treatments can lead to dose-limiting toxicity and significant side-effects, limiting their application.
Therefore, there remains in the art an evident need for new and more effective anti-HIV agents. Within this general desire, the identification of drugs other than protease inhibitors and nucleoside reverse transcriptase and drugs that target other important process in the HIV life cycle are needed. The identification of a drug that acts against a cellular target would be an important advance in the field, particularly as such a drug would make it difficult for resistant strains to arise.
The present invention addresses the foregoing long-felt need and other deficiencies in the art by identifying new and effective strategies for treating viral infections, particularly HIV infections and AIDS. The invention is based, in part, upon the discovery that the compound flavopiridol, used in clinical trials for the treatment of cancer, dramatically inhibits the transcription elongation factor, P-TEFb. As P-TEFb is required for HIV propagation and replication in human cells, flavopiridol compounds can now be used to inhibit cellular P-TEFb, thus interfering with HIV replication and providing new treatments for HIV infections and AIDS.
The invention thus provides new methods, compositions, kits and uses for treating HIV infections and AIDS using flavopiridol compounds and, optionally, combinations of such compounds with other HIV therapeutics. One particularly surprising aspect of this invention is the fact that the cellular targets for flavopiridol action were thought to have been identified, leaving no motivation to search for other candidate molecules to which flavopiridol may bind or inhibit.
A further unexpected benefit of the invention is the ability of flavopiridol to inhibit P-TEFb, and consequent HIV infection, at extremely low concentrations. This allows flavopiridol compounds to be used in HIV treatment at concentrations that are much lower than those employed to produce an anti-tumor effect, thus providing HIV and AIDS treatments with reduced or absent side-effects and toxicities. In fact, the effectiveness of flavopiridol in inhibiting P-TEFb and HIV infection is such that the present invention provides pharmaceutical compositions comprising surprisingly low, but nonetheless therapeutically effective, levels of flavopiridol.
The invention thus provides a variety of flavopiridol-based compositions and methods for inhibiting the enzyme complex P-TEFb (positive transcription elongation factor b). As used herein, unless otherwise stated or evident from scientific usage, the term xe2x80x9cP-TEFbxe2x80x9d is employed to mean a functional, operative enzyme complex with biological activity. In structural terms, the P-TEFb enzyme complex is comprised of a cyclin-dependent kinase subunit (Cdk9) and a larger, cyclin subunit (cyclin T1). Again, unless otherwise stated or scientifically evident, the xe2x80x9cP-TEFbxe2x80x9d of the present disclosure comprises both the kinase (Cdk9) and cyclin (cyclin T1) subunits.
According to the convention in the art, as used herein, unless otherwise stated or made evident, the term xe2x80x9cHIVxe2x80x9d is often used succinctly to refer to xe2x80x9cHIV-1xe2x80x9d. Those of ordinary skill in the art will understand that where xe2x80x9cHIV-2xe2x80x9d is particularly intended, this will be recited. In the absence of such direction, xe2x80x9cHIVxe2x80x9d may include xe2x80x9cHIV-1 and HIV-2xe2x80x9d, with xe2x80x9cHIV-1xe2x80x9d being particularly preferred for treatment by the invention.
Currently, the most preferred flavopiridol-like compound is flavopiridol itself. Flavopiridol is 4H-1-Benzopyran-4-one,2-(2-chlorophenyl)-5,7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, hydrochloride, (xe2x88x92)-cis-; which may also be termed (xe2x88x92)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8-[4R(3 S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one, hydrochloride.
However, those of ordinary skill in the art will understand that the present invention is by no means limited to the use of flavopiridol itself, but encompasses a range of xe2x80x9cflavopiridol-like compoundsxe2x80x9d, such as analogs and derivatives. Exemplary flavopiridol compounds other than the parent flavopiridol compound include 2-thio and 2-oxo flavopiridol analogs. Any flavopiridol-based compound may be used in the invention so long as it inhibits P-TEFb in at least substantially the same manner as flavopiridol itself. Given the mechanistic studies provided herein, flavopiridol compounds that inhibit P-TEFb to a greater extent, and/or with other advantageous properties, can now be designed and used in the present invention.
Irrespective of the source of the flavopiridol-based compounds, the invention particularly contemplates the use of one, two, three or four distinct flavopiridol analogues or derivatives, up to and including a plurality of such compounds. This exemplifies the use of singular terminology throughout the entire application, wherein the terms xe2x80x9caxe2x80x9d and xe2x80x9canxe2x80x9d are used in the sense that they mean xe2x80x9cat least onexe2x80x9d, xe2x80x9cat least a firstxe2x80x9d, xe2x80x9cone or morexe2x80x9d or xe2x80x9ca pluralityxe2x80x9d of the referenced components or steps, except in instances wherein an upper limit is thereafter specifically stated or would be understood by one of ordinary skill in the art. The operable limits and parameters of combinations, as with the amounts of any single agent, will be known to those of ordinary skill in the art in light of the present disclosure.
By the term xe2x80x9cinhibitingxe2x80x9d, it is meant that practice of the present invention results in the xe2x80x9cinhibitionxe2x80x9d of P-TEFb, preferably the inhibition of one or more of the xe2x80x9cbiological activitiesxe2x80x9d of P-TEFb. Most preferably, the inhibition takes the form of ultimately inhibiting the role of P-TEFb in transcription.
Although by no means bound by the following mechanism, the present inventors believe that the invention functions due to the inhibition of the cyclin-dependent kinase (cdk9) subunit of P-TEFb. Once inhibited, the cdk9 kinase subunit is unable to effectively phosphorylate RNA polymerase II, thus inhibiting transcription. However, any form of xe2x80x9cinhibitionxe2x80x9d of P-TEFb is encompassed by the present invention. As advantageous aspects of the invention concern net inhibitory effects observed at the whole cell or whole animal level, an understanding of the precise molecular mechanism by which the invention operates, although of scientific interest, is not necessary to practice the invention as disclosed herein.
In order to inhibit P-TEFb in accordance with the invention, the inhibitory methods may be conducted at the sub-cellular or cellular levels or in the context of the whole animal, including clinical treatment. All such methods involve the xe2x80x9cprovisionxe2x80x9d of at least a first flavopiridol compound to the environment of the P-TEFb in a manner effective to xe2x80x9ccontactxe2x80x9d the P-TEFb with an effective inhibitory amount of the flavopiridol compound.
One method to inhibit P-TEFb comprises contacting xe2x80x9ccell-free P-TEFbxe2x80x9d, i.e., contacting a cell-free composition that comprises P-TEFb, with an effective inhibitory amount of at least a first flavopiridol compound. The operation of such methods generally involves providing to a cell-free system that comprises P-TEFb an amount of a flavopiridol compound effective to inhibit the cyclin-dependent kinase (cdk9) subunit of P-TEFb.
In such sub-cellular methods, the cell-free system may comprise components effective to achieve measurable RNA polymerase II phosphorylation. The inhibition of P-TEFb activity can thus be readily determined by measuring the inhibition of RNA polymerase II phosphorylation in the cell-free system. Preferably, in such methods, the cell-free system comprises components effective to perform measurable in vitro transcription, whereby the inhibition of P-TEFb may be readily determined by measuring the inhibition of transcription elongation in the cell-free system. Such xe2x80x9ckinasexe2x80x9d and xe2x80x9ctranscriptionxe2x80x9d assays are known to those of ordinary skill in the art and are further described herein.
In other in vitro embodiments, the inhibitory methods of the invention are performed using intact cells and populations thereof. Examples of such methods include those for generally inhibiting transcription, which comprise providing to a cell capable of supporting transcription an amount of at least a first flavopiridol compound effective to inhibit transcription in the cell. The inhibition of transcription in this manner is particularly embodied by inhibiting transcription via RNA polymerase II.
The foregoing and other sub-cellular and cellular inhibitory methods of the invention, including the xe2x80x9ckinasexe2x80x9d and xe2x80x9ctranscriptionxe2x80x9d inhibition, have definite practical uses, such as in providing reliable controls for performing in vitro studies, known to be necessary components in drug screening assays and the like.
In further embodiments, the invention provides compositions and methods for inhibiting P-TEFb in which the flavopiridol compound is provided to a virally-infected cell, resulting in the inhibition of the cdk9 subunit of the P-TEFb within the cell. These methods are intelligently applied in inhibiting viral transcription, in which the flavopiridol compound is provided to a cell capable of supporting viral transcription and wherein viral transcription is inhibited in the cell.
The cells and virally-infected cells to be acted upon by the invention are preferably mammalian cells, although they need not be, with particular examples being primate and human cells. Other aspects of the invention are therefore human cells, and populations thereof, comprising components of an HIV virus and a biologically effective amount of at least a first flavopiridol compound.
The inhibition of viral transcription may be performed in vitro, such that at least a first flavopiridol compound is provided to a system or cell competent to perform viral transcription, resulting in inhibition of viral transcription. An exemplary xe2x80x9csystem competent to perform viral transcriptionxe2x80x9d is a cell comprising a genetic construct that expresses a reporter gene from a viral promoter. The inhibition of viral transcription in such a cell or system is readily determined by measuring the inhibition of reporter gene expression in the cell or system. Such methods are exemplified using HIV transcription and CMV transcription, but are widely applicable to a range of viral transcription.
Throughout the methods of the invention, an xe2x80x9ceffective inhibitory amountxe2x80x9d is an amount of at least a first flavopiridol compound effective to inhibit, and preferably to significantly inhibit, P-TEFb. The effective inhibitory amounts are thus also amounts effective to inhibit, and preferably to significantly inhibit, a biological activity of P-TEFb, such as inhibiting transcription, and preferably, inhibiting viral transcription. More preferably, the effective inhibitory amounts are amounts of flavopiridol compounds effective to inhibit, and preferably to significantly inhibit, viral transcription, replication and/or propagation in virally-infected cells. Any degree of inhibition is sufficient to satisfy the invention, although those of ordinary skill in the art will understand the inhibition levels that are sufficient to indicate preferred in vitro and in vivo inhibition.
xe2x80x9cInhibitionxe2x80x9d requires a xe2x80x9creproduciblexe2x80x9d, i.e., consistently observed, inhibition in one or more of the foregoing parameters. A xe2x80x9csignificant inhibitionxe2x80x9d is a reproducible or consistently observed significant inhibition in one or more of the foregoing parameters, such as a reproducible inhibition of at least about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% in comparison to control levels, i.e., in the absence of flavopiridol. Although not required to practice the invention, inhibition levels of at least about 85%, about 90%, about 95% or even higher are by no means excluded.
Further methods of the invention concern the xe2x80x9cdifferential inhibitionxe2x80x9d of cellular or host gene transcription as opposed to viral gene transcription. As the present invention shows a surprisingly effective degree of differential inhibition, particularly in terms of HIV infection of human cells, all that is required to practice these aspects of the invention is to provide to a cell capable of supporting host and viral transcription an amount of at least a first flavopiridol compound effective to inhibit viral gene transcription in preference to cellular or host gene transcription in the cell.
Such is the basic meaning of a xe2x80x9cdifferentially inhibiting amountxe2x80x9d, as used herein. Preferably, a xe2x80x9cdifferentially inhibiting amountxe2x80x9d is an amount of at least a first flavopiridol compound effective to significantly inhibit viral transcription, replication and/or propagation in virally-infected cells of a host without significantly inhibiting host cell gene transcription and cellular function in equivalent, non-virally-infected host cells.
Although by no means a requirement of the invention, the differential inhibition methods provide for certain important uses of this discovery. The inhibition of viral gene transcription to a greater degree than host cell gene transcription supports the in vitro and in vivo anti-viral methods and compositions of the present invention.
Accordingly, the invention provides methods for inhibiting viral gene transcription, comprising providing to a virally-infected cell an amount of at least a first flavopiridol compound effective to inhibit the cdk9 subunit of P-TEFb within the cell, thus inhibiting viral transcription in the cell. Important target cells in these aspects are HIV-1-infected cells. However, as P-TEFb is required for HIV-2, EIAV (equine infections anemia virus), SIV (simian immunodeficiency virus) and BIV (bovine immunodeficiency virus) functions in host cells, the present invention provides effective compositions and methods to inhibit viral gene transcription in cells and animals infected with HIV-2, EIAV, SIV and BIV.
As viral transcription is an essential step of viral replication and propagation, the present invention further provides compositions and methods for inhibiting viral replication and/or propagation. Such methods generally comprise providing to a cell infected, or suspected of being infected, with a virus an amount of at least a first flavopiridol compound effective to inhibit P-TEFb within the cell, thereby inhibiting viral transcription, replication and/or propagation in the cell. Preferred aspects of the invention again concern the inhibition of HIV-1 replication and/or propagation, although inhibiting the replication and/or propagation of viruses such as HIV-2, EIAV, SIV and BIV is encompassed by the present invention.
The inhibition of viral transcription, replication and/or propagation is unified in that it may be achieved in vitro or in vivo. To practice these aspects of the invention in vivo, the virally-infected cell is located within an animal or patient and the at least a first flavopiridol compound is provided to the animal or patient in a manner and an amount effective to contact the virally-infected cell with the inhibitory flavopiridol compound. Preferably, the amount is an amount effective to inhibit viral transcription, replication and/or propagation in virally-infected cells of the animal. More preferably, the amount is a differentially inhibiting amount that is effective to significantly inhibit viral transcription, replication and/or propagation in virally-infected cells of the animal without significantly inhibiting host cell gene transcription or cellular integrity.
Accordingly, the invention provides compositions and methods for inhibiting P-TEFb in an animal or patient, which generally comprise providing to an animal or patient having, suspected of having, or at risk for developing a viral infection, an amount of at least a first flavopiridol compound effective to inhibit P-TEFb within cells of the animal or patient.
Execution of these methods leads to methods for preventing or treating a viral infection, comprising providing to an animal or patient having, suspected of having, or at risk for developing a viral infection, an amount of at least a first flavopiridol compound effective to inhibit P-TEFb within cells of the animal or patient, thereby preventing or treating the viral infection. The P-TEFb should particularly be inhibited within the virally infected or susceptible cells of the animal or patient, as exemplified by the inhibition of P-TEFb within T cells and/or macrophages, which are infected, or are susceptible to infection, by HIV-1.
The animals to be treated by the invention are preferably mammals or primates, with the invention being particularly suitable for treating HIV-1, HIV-2, EIAV, SIV and BIV infections and the associated and resultant diseases.
The treatment of humans with HIV-1 infections and resultant diseases is particularly preferred. Accordingly, the invention provides methods for preventing or treating an HIV-1 infection, comprising providing to a subject or patient having, suspected of having, or at risk for developing an HIV-1 infection, an amount of at least a first flavopiridol compound effective to inhibit P-TEFb within cells of the subject or patient, thereby preventing or treating the HIV-1 infection.
Where xe2x80x9cpreventionxe2x80x9d is concerned, whether of HIV-1 or other viral infections, the amounts of flavopiridol compounds are xe2x80x9cprophylactically effective amountsxe2x80x9d, such that they are effective to inhibit P-TEFb within cells of the animal or subject, thereby preventing or retarding the development of the infection, lessening its severity and/or duration or such like. Where xe2x80x9ctreatmentxe2x80x9d is concerned, whether of HIV-1 or other viral infections, the amounts of flavopiridol compounds are xe2x80x9ctherapeutically effective amountsxe2x80x9d, such that they are effective to inhibit P-TEFb within cells of the animal or patient, thereby treating the infection, as exemplified by alleviating symptoms, lessening the severity and/or duration of the infection, up to and including curing the infection or disease.
In certain aspects, the invention thus provides methods for slowing or preventing an HIV infection, comprising identifying a subject at risk for developing an HIV infection and administering to the subject a prophylactically effective amount of at least a first flavopiridol compound. Methods for slowing or preventing the progression of an HIV infection into full-blown AIDS are also provided, comprising providing to a patient having an HIV infection an amount of at least a first flavopiridol compound effective to inhibit P-TEFb within cells of the patient, thereby slowing or preventing the progression of the HIV infection into full-blown AIDS.
Other methods are those for treating an HIV infection, comprising providing to a subject having or suspected of having an HIV infection an amount of at least a first flavopiridol compound effective to inhibit P-TEFb within T cells and/or macrophages of the subject, thereby treating the HIV infection. Other methods for treating a patient with an HIV infection, comprise providing at least a first flavopiridol compound to such a patient in an amount and for a period of time effective to inhibit the cyclin-dependent kinase (cdk9) subunit of P-TEFb within HIV-infected cells of the patient, thereby inhibiting HIV replication or HIV propagation in the patient.
Yet further methods of the invention are those for treating patients with an AIDS related illness or full-blown AIDS, comprising providing to the patient an amount of one or more flavopiridol compounds effective to inhibit P-TEFb within a number of cells of the patient sufficient to exert a therapeutic effect in the patient. The patients may be identified or pre-selected by any one or more of a number of means.
Given the effectiveness of the invention, another advantage is that it provides compositions and methods for treating patients infected with a strain of HIV-1 that is at least moderately resistant to at least a first available anti-HIV therapeutic agent. These methods extend to the treatment of patients infected with a strain of HIV that is substantially resistant to at least a moderate number of available anti-HIV therapeutic agents.
The foregoing xe2x80x9cprophylactically and therapeutically effective amountsxe2x80x9d are thus encompassed within the terms xe2x80x9cbiologically effective amountsxe2x80x9d and xe2x80x9ceffective inhibitory amountsxe2x80x9d of flavopiridol compounds. All such xe2x80x9ceffective amountsxe2x80x9d are amounts of flavopiridol compounds effective to produce some, and preferably some significant, benefit upon administration to an animal or patient. The benefits include reducing symptoms, severity and/or duration, as well as lessening the chance of transmission and other veterinary and clinical benefits.
It will be understood that the more significant the disease to be treated, the more side-effects that can likely be tolerated. Equally, where the disease to be treated is not particularly significant or life-threatening, the lack of side-effects should be more stringently pursued.
Appropriate doses will be known those of ordinary skill in the art in light of the present disclosure. For example, suitable doses of flavopiridol compounds are those provided to patients in an amount between about 4 mg/m2/day IV over 72 hours (5 mg/kg PO) and about 50 mg/m2/day IV over 72 hours (25 mg/kg PO); between about 12 mg/m2/day IV over 72 hours (10 mg/kg PO) and about 28 mg/m2/day IV over 72 hours (20 mg/kg PO); and between about 8 mg/m2/day IV over 72 hours (8 mg/kg PO) and about 16 mg/m2/day IV over 72 hours (15 mg/kg PO). Further suitable doses are those effective to produce a peak plasma concentration of between about 30 nM and about 60 nM upon administration to a human subject.
The routes of administration that may be used in the present invention are virtually limitless, so long as an effective amount of at least a first flavopiridol compound can be provided thereby. Exemplary means include ingestible, oral administration and parenteral administration, such as by intranasal administration, subcutaneous injection, intravenous injection or continuous infusion.
All such compositions and methods of the invention may be combined for use with one or more other anti-viral agents, such as at least a second, third, fourth or fifth, anti-HIV agent or at least a first, second, third or fourth anti-AIDS therapeutic agent. A plurality of distinct anti-HIV or anti-AIDS therapeutic agents may be administered to an animal or patient, up to and including the dose limiting toxicity of the combination. The invention can thus be used to form synergistic combinations with other therapies and/or known agents, particularly those methods and agents that previously failed to achieve maximal effectiveness in vivo, perhaps due to dose-limiting toxicity and/or viral resistance.
In terms of anti-HIV and anti-AIDS therapeutic agents, certain preferred compounds include nucleoside analogue reverse transcriptase inhibitors (NRTIs) and protease inhibitors. Particular exemplary compounds include those selected from the group consisting of amprenavir (Agenerase(trademark)); the VX-175/GW433908 prodrug of amprenavir (Agenerase(trademark));
Combivir(copyright); indinavir (Crixivan(trademark)); lamivudine (3TC, Epivir(trademark)); saquinavir (Invirase(trademark) or Fortovase(trademark)); zalcitabine (ddC, Hivid(trademark)); hydroxyurea (Hydrea(trademark)); ritonavir (Norvir(trademark)); adefovir dipivoxil (Preveon(trademark)); delavirdine (Rescripto(trademark)); AZT (zidovudine, Retrovir(trademark)); efavirenz (Sustiva(trademark)); didanosine (ddI, Videx(trademark)); nelfinavir (Viracept(trademark)); nevirapine (Viramune(trademark)); stavudine (d4T, Zerit(trademark)); abacavir (Ziagen(trademark)); capravirine (AG1549) and emivirine (MKC-442, Coactinon(copyright)).
In such combination therapies, the at least a first flavopiridol compound and at least a second anti-HIV or anti-AIDS therapeutic agent may be administered to the animal or patient substantially simultaneously, such as from a single pharmaceutical formulation or two distinct pharmaceutical formulations. Alternatively, the at least a first flavopiridol compound and at least a second anti-HIV or anti-AIDS therapeutic agent may be administered to the animal or patient sequentially, such as on alternate days.
In further embodiments, the invention provides a range of therapeutic kits. Certain kits comprise a therapeutically effective amount of at least a first flavopiridol compound and instructions for administering the flavopiridol compound to an animal or subject having or at risk for developing an viral infection, HIV infection or AIDS. Such kits may be combined with effective amounts of at least one diagnostic agent that detects a viral, HIV infection or AIDS; or with a therapeutically effective amount of at least one other anti-viral, anti-HIV or anti-AIDS therapeutic agent.
Certain other therapeutic kits of the invention comprise an effective amount of at least a first flavopiridol compound and an effective amount of at least one diagnostic agent that detects a viral, HIV infection or AIDS; or an effective amount of at least one, two, three, four or any number of other anti-viral, anti-HIV or anti-AIDS therapeutic agents. Instructions may also be combined with these kits. Other biological agents or components may be included, such as those for making and using the drugs.
Exemplary diagnostic agents include molecular biological agents that detect at least a first HIV nucleic acid; at least a first antibody that detects at least a first HIV protein or peptide; and at least a first HIV protein or peptide that detects at least a first antibody that binds to an HIV protein or peptide. The range of additional therapeutic agents will be known those of ordinary skill in the art in light of the present disclosure, as exemplified by those described herein.
In such kits, the diagnostic agents are preferably disposed within a distinct container of the kit. The combined therapeutic agents, however, may be combined within a single container of the kit, i.e., in the same composition as the flavopiridol compound, such as in a cocktail or admixture. They may alternatively be maintained separately from the flavopiridol compound, in a distinct container.
The invention thus provides combination therapeutics comprising, in any pharmaceutically acceptable form, a therapeutically effective amount of a flavopiridol compound in combination with a therapeutically effective amount of at least a second anti-viral, anti-HIV or anti-AIDS therapeutic agent. Also provided are medicinal cocktails comprising, in any pharmaceutically acceptable form, a combined therapeutically effective amount of flavopiridol or a flavopiridol analog or derivative and a plurality of distinct anti-viral, anti-HIV or anti-AIDS therapeutic agents.
Further important aspects of the invention are compositions comprising a dilute solution of at least a first flavopiridol compound, optionally in combination with a pharmaceutically acceptable excipient, e.g., one suitable for oral or intranasal administration, or for parenteral administration, such as intravenous or subcutaneous injection or continuous infusion. Such compositions may comprise at least a first flavopiridol compound at a concentration of between about 0.01 mg/ml and about 0.04 mg/ml.
Particular novel and inventive compositions of the invention are those comprising a therapeutically effective amount of at least a first flavopiridol compound formulated for oral administration and those comprising a therapeutically effective amount of at least a first flavopiridol compound formulated for intranasal administration.
Yet further compositions of the invention are those comprising at least a first flavopiridol or flavopiridol analog formulated in a unit low dose solution for any type of administration. Exemplary unit low dose flavopiridol solutions are those effective to significantly inhibit the cyclin-dependent kinase (cdk9) of P-TEFb without significantly inhibiting other cyclin-dependent kinases. Further exemplary compositions are those comprising a solution of at least a first flavopiridol compound effective to produce a peak plasma concentration of between about 30 nM and about 60 nM upon administration to a human subject.
Naturally, the invention further provides any type of flavopiridol composition for use in treating a viral or HIV infection or AIDS. The invention yet further provides for the use of any type of flavopiridol composition in the manufacture of a medicament for use in treating a viral or HIV infection or AIDS. Combined uses and medicaments in which a flavopiridol compound is one component of a therapeutic approach are also encompassed within the present invention.